Article

Human bone marrow hematopoietic stem cells are increased in frequency and myeloid-biased with age

Institute for Stem Cell Biology and Regenerative Medicine, Ludwig Center for Stem Cell Research, and Department of Pathology, Stanford University, Stanford, CA 94305, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 11/2011; 108(50):20012-7. DOI: 10.1073/pnas.1116110108
Source: PubMed

ABSTRACT In the human hematopoietic system, aging is associated with decreased bone marrow cellularity, decreased adaptive immune system function, and increased incidence of anemia and other hematological disorders and malignancies. Recent studies in mice suggest that changes within the hematopoietic stem cell (HSC) population during aging contribute significantly to the manifestation of these age-associated hematopoietic pathologies. Though the mouse HSC population has been shown to change both quantitatively and functionally with age, changes in the human HSC and progenitor cell populations during aging have been incompletely characterized. To elucidate the properties of an aged human hematopoietic system that may predispose to age-associated hematopoietic dysfunction, we evaluated immunophenotypic HSC and other hematopoietic progenitor populations from healthy, hematologically normal young and elderly human bone marrow samples. We found that aged immunophenotypic human HSC increase in frequency, are less quiescent, and exhibit myeloid-biased differentiation potential compared with young HSC. Gene expression profiling revealed that aged immunophenotypic human HSC transcriptionally up-regulate genes associated with cell cycle, myeloid lineage specification, and myeloid malignancies. These age-associated alterations in the frequency, developmental potential, and gene expression profile of human HSC are similar to those changes observed in mouse HSC, suggesting that hematopoietic aging is an evolutionarily conserved process.

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    • "Loss of Wnt and T-cell potential in aged human HSCs, M. L. M. Khoo et al. capability for specification to the myeloid lineage, but insufficient levels for T-lymphocyte differentiation. In addition, this intrinsic defect in Wnt signaling of aged human HSCs may contribute to the reported myeloidbiased skewing of differentiation potential that is associated with aging of the hematopoietic system (Pang et al., 2011). Interaction or cross talk between the Notch and Wnt signaling pathways has been reported with increasing frequency (Munoz Descalzo & Martinez Arias, 2012). "
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    • "Further, aged HSCs show a differentiation preference toward myeloid lineages at the expense of lymphoid differentiation (Morrison et al., 1996; Sudo et al., 2000; Liang et al., 2005; Rossi et al., 2005; Chambers et al., 2007). In humans, aged HSCs also show increased frequency and a bias toward myeloid potential (Pang et al., 2011). "
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